DESCRIPTION (Adapted from the applicant?s abstract) The most effective contemporary lipid lowering regimens reduce the major manifestations of atherosclerosis by at most a third. Thus, the majority of cardiovascular events occurred despite effective management of low density lipoprotein cholesterol. Moreover, there is a wide range of expression of atherosclerotic complications in individuals with similar profiles of traditional risk factors. Also, the episodic nature of the evolution and manifestations of atherosclerosis remains unexplained by simple consideration of the systemic risk factors long implicated in atherogenesis. Considerable sero-epidemiological evidence links infectious processes with cardiovascular risk. Additionally, current thought highlights inflammatory mechanisms as major contributors to atherogenesis and in the precipitation of the clinical manifestations of atherosclerosis. Project 1 will link these disparate observations into a unifying hypothesis. We postulate that infectious agents may potentiate traditional risk factors, heightening atherogenesis and contributing to the triggering of its acute manifestations. Recent evidence has clearly localized Chlamydia pneumoniae within human atherosclerotic plaques. The laboratory has used bacterial products such as Gram-negative lipopolysaccharide as a model stimulus to probe the inflammatory functions of vascular wall cells for over a dozen years. This project will therefore address the specific hypothesis that components of chlamydia pneumoniae may activate inflammatory functions of vascular wall cells and leukocytes such as macrophages and lymphocytes which infiltrate atherosclerotic plaques. The pilot data suggest that heat shock proteins derived from the Chlamydia organism, and localized by us in many human atherosclerotic lesions, indeed elicit the production of pro-inflammatory cytokines by macrophages in vascular wall cells. This surprising finding has implications beyond atherogenesis, as heat shock proteins are generally considered intracellular mediators. This project will probe the mechanism of the effect of externally applied hat sock protein 60 that has been observed, and aspect of this project that should lead to new information of biological significance aside from the consideration of a role of infectious agents in cardiovascular diseases. This project will also explore the hypothesis that chlamydia pneumoniae may elicit a specific immune response in atherosclerotic mice in vivo, providing a potential novel candidate antigen for the cellular immune response now known to characterize human atherosclerosis. The investigation of the immune response to Chlamydia pneumoniae will include testing the possibility of antigenic mimicry as a possible immuno-pathogenic mechanism operating in the artery wall. This project, although new, emerges from a long standing interest of the project leader in inflammatory and immune aspects of vascular diseases. This project does not however contend that atherosclerosis is an infectious disease. Rather, it views infectious agents as a potential co-factor acting in concert with traditional risk factors such as dyslipidemia to potentiate atherogenesis and trigger atherosclerotic complications. The accumulating sero-epidemiological evidence and even clinical trials with antibiotics will neither establish the casual relationship between bacterial infections and atherogenesis nor elucidate the potential underlying mechanisms. The hypotheses probed in Project 1 aim to adduce new mechanistic information with implications for vascular biology and atherogenesis of general import, not limited to specific infectious processes. This project links closely with the concepts under scrutiny in Project 2. Specifically, this project will test the hypothesis that bacterial products including Chlamydia heat shock protein 60 can evoke or modulate aspects of the oxidative stress response in endothelial cells. The generation of the pilot data that furnishes the basis for this proposal used resources form the Vascular Pathology Core of the predecessor Program project. This project will continue to rely heavily on this Core. The focus on inflammatory mechanisms links conceptually with aspects of project 3 as well.